Historical Notes

The first description of Cushing’s syndrome dates back to 1899 when William Osler presented a patient with “an acute mixoedematous condition,” which he ascribed to thyroid gland dysfunction, but in hindsight was actually due to excess glucocorticoid secretion.¹ Some 10 years later, Harvey Cushing summarized the symptoms featured in his namesake syndrome and established the causative link with “pituitary basophilism.” The second case in his landmark monograph, however, was ascribed to an adrenal disorder, and he himself recognized that the syndrome of “diabetes in bearded women” was often associated with hyperplasia or tumors of the suprarenal glands.² In 1934, Walters et al. demonstrated that removal of the adrenals was curative in these patients,³ thus validating the importance of the adrenal gland as a target of pituitary hyperproduction or primary cause of glucocorticoid excess. This distinction was by no means straightforward; pituitary Cushing’s disease was also being called “ACTH-dependent adrenal hyperplasia,” necessitating bilateral adrenalectomy, and “nodular adrenal hyperplasia” was considered partially ACTH dependent.

Over time, primary adrenal Cushing’s syndrome finessed its etiologic status, thanks in part to the widespread availability of radioimmunoassay measurements, and adrenal autonomy became associated with suppressed ACTH levels rather than nodular adrenal morphology. The importance of aberrant or inappropriate receptors as causative factors for bilateral adrenal hyperplasia, the isolation of genes linked with PPNAD, and the identification of molecular markers for the distinction between malignant and benign adrenal tumors are all recent developments in the field of adrenal Cushing’s syndrome.

Epidemiology

Cushing’s syndrome is a rare disease. Its incidence has been estimated at around 2 to 10 patients per million population per year, with less than half due to adrenal causes.4,5 Of interest, adrenal adenomas appear to affect the Japanese population with greater frequency, reportedly presenting over 20 new patients per million per year.⁶ The ratio between benign and malignant adrenal tumors varies from roughly equal in some series^5,7 to 10:1 in Japanese studies.⁶ Oncologic surveys report an annual incidence of adrenal neoplasms of around 2 per million^8,9 and 0.6 to 1 per million for adrenocortical cancer.⁸ Approximately one third of these patients will present with Cushing’s syndrome,^10,11 resulting in 0.2 to 0.3 cortisol-secreting adrenal cancers per million per year, which tallies nicely with estimates garnered from endocrinologic studies.⁵

Age and gender distribution vary somewhat between the different adrenal etiologies of Cushing’s syndrome, with adrenal cancer presenting a bimodal distribution (peak in childhood/adolescence then again after 45 years of age), and adrenal adenoma occurring mostly in young adults (25 to 45 years of age) (Fig. 7-1). PPNAD gives rise to hypercortisolism during infancy and adolescence in over half of cases,¹² whereas ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) has been reported mostly in adults older than 50.^13,14 Adrenal Cushing’s syndrome in the majority of adult patients is due to benign adenomas (50% to 80%, according to different series). Adrenal-cortex carcinoma accounts for another 20%, and a scattering of cases are due to ACTH-independent adrenal hyperplasia and PPNAD.^15,16 Conversely, in childhood, malignant forms make up the major share, the remainder due to adenomas or even genetic causes such as PPNAD or MAS.^12,17

Adrenal adenoma occurs mostly in females, as does—to a lesser extent—cortisol-secreting adrenal cancer.5,18,19 No clear-cut sex-related pattern has been observed for Cushing’s associated with AIMAH and PPNAD.

Mortality from untreated Cushing’s syndrome is high, with 50% survival 5 years after the diagnosis,²⁰ mostly due to cerebrovascular events and infections. Upon removal of a benign adenoma, taking perisurgical mortality into consideration, 5-year survival averaged 77%²¹ in the 1980s, but is nowadays comparable to mortality in the general population.^5,22 As regards mortality from malignant adrenocortical cancer, outcome is dismal, with high mortality for stage III and IV disease and slightly better survival for patients diagnosed with localized disease.^23–25 In Cushing’s syndrome due to PPNAD within Carney’s complex, a familial multiple endocrine neoplasia syndrome, extraendocrine manifestations such as cardiac myxomas or malignant Schwannomas contribute to excess mortality.²⁶

Diagnosis of Cushing’s Syndrome

The diagnosis of Cushing’s syndrome due to adrenal tumors is first raised by the clinical presentation then confirmed by both biochemical and radiologic investigations. Hormonal measurements reflect the functional derangement of the hypothalamo-pituitary-adrenal (HPA) axis consequent to sustained autonomous cortisol production by the adrenal gland. Two features of the HPA axis are relevant to pathophysiology of primary adrenal hypercortisolism: (1) homeostasis of the HPA axis is assured through long and short feedback loops acting at hypothalamic (i.e., corticotropin-releasing hormone [CRH]), pituitary (i.e., ACTH), and adrenal (i.e., cortisol) levels, with cortisol levels as the effector of feedback; (2) cortisol and ACTH are secreted in pulsatile fashion, inscribed within a circadian rhythm with high secretory output in the early morning, progressive decrease during the day, and nadir around midnight. If adrenal cortisol production is autonomous, as occurs in adrenal-derived Cushing’s syndrome, high steroid secretion will activate negative-feedback loops leading to suppression of hypothalamic and pituitary secretion and thus disruption of physiologic pulsatility and circadian rhythmicity of ACTH and cortisol secretion. The HPA axis will also be resistant to further inhibition by exogenous steroids. The diagnosis of Cushing’s syndrome is performed by looking for these alterations: evaluation of integrated daily cortisol secretion and its circadian rhythmicity and suppressibility with dexamethasone. Details of these investigations are given elsewhere, but specific changes expected in adrenal-driven disease are given in following discussions.

Urinary free cortisol (UFC) levels are usually very high in patients with adrenocortical cancer (up to 100 times greater than normal), whereas such striking elevations are less frequent in patients with cortisol-secreting adenoma (Fig. 7-4). Indeed, UFC concentrations may occasionally fall within the normal range in these latter patients,²⁷ and this underlines the need for multiple UFC measurements.^33,34 In patients with AIMAH, UFC concentrations are rarely very high and may fluctuate according to stimulation by the causative aberrant receptor. For example, patients in whom hypercortisolism was dependent upon adrenal cortex stimulation by LH, who exhibit markedly elevated UFC concentrations and develop Cushingoid features only during pregnancy and menopause.^35,36 In young patients with PPNAD, again, UFC rarely reaches very high levels and may present slow, periodic progression.^12,37,38 Other tests usually involve assessment of cortisol daily variations or its suppressibility by dexamethasone. In patients with full blown hypercortisolism, two clearly pathologic results or even one are sufficient to establish the diagnosis of Cushing’s syndrome and proceed with the diagnostic workup. However, in patients with mildly elevated or fluctuating cortisol values (as often occurs with AIMAH or even PPNAD), repeat evaluations over time are necessary. A secure diagnosis of Cushing’s syndrome is essential before performing tests for the etiologic diagnosis of hypercortisolism, because the results obtained with these procedures may overlap with normal physiology.

Diagnosis of Adrenal Cushing’s Syndrome

Once the existence of Cushing’s syndrome is firmly established, the etiology of the disease has to be defined. In adrenal Cushing’s syndrome of any given etiology, autonomous cortisol secretion by the adrenals feeds back at hypothalamo-pituitary level to inhibit CRH and ACTH secretion. Plasma ACTH levels will therefore be suppressed in adrenal Cushing’s syndrome, whereas inappropriately high ACTH concentrations characterize ACTH-dependent Cushing’s syndrome (i.e., pituitary or ectopic ACTH secreting tumor. Measurement of plasma ACTH levels is therefore pivotal to the differentiation of ACTH-dependent from ACTH-independent Cushing’s syndrome. As mentioned above, ACTH is secreted in pulsatile fashion, dictating the same circadian rhythm to cortisol. Further, ACTH is extremely sensitive to stress, has a short plasma half life, and is easily degraded by plasma peptidases. For these reasons, blood samples for ACTH measurement have to be collected in unstressed conditions, preferably two or three samples over 30 minutes, into tubes containing enzyme inhibitors and conserved at low temperatures prior to separation into aliquots. Repeated freeze/thaw cycles should be avoided.

In the vast majority of patients with adrenal Cushing’s syndrome, plasma ACTH concentrations are suppressed, thus providing clear distinction from ACTH-dependent Cushing’s syndrome. Initially formulated guidelines indicated that morning ACTH concentrations lower than 10 pg/mL (2 pmol/L) or evening ACTH levels lower than 5 pg/mL (1 pmol/L) were indicative of ACTH-independent Cushing’s syndrome.³⁹ In RIA assays with 5 to 10 pg/mL sensitivity, this corresponds to values below the detection limit. With the newly developed IRMA or chemiluminescent assays capable of measuring plasma ACTH concentrations as low as 1 pg/mL (0.2 pmol/L), ACTH values may be detectable in patients with adrenal Cushing’s syndrome but usually are below the lower limit of the normal range.^16,27,40,41 However, in an Italian study on over 50 patients with adrenal Cushing’s syndrome, up to one fourth presented ACTH concentrations within the normal range²⁷ (Fig. 7-5), but whether this is because of issues in assay methodology, as seems more likely, or to incomplete suppression of pituitary ACTH secretion remains to be established. Occasionally, ACTH concentrations are frankly non-suppressed^40,42,43; in one patient bearing an adrenal carcinoma, ACTH concentrations were persistently high because the tumor itself produced ACTH.⁴⁴ In addition to patients with adrenal Cushing’s syndrome presenting measurable or normal ACTH concentrations, some 10% of patients with Cushing’s disease display ACTH values below 10 pg/mL (2 pmol/L),²⁷ thus blurring the boundaries between the two etiologies. To correctly diagnose patients falling into this grey area, stimulation with CRH proves of use; patients with pituitary-dependent hypercortisolism will mount an ACTH response to the stimulus, whereas patients with ACTH-independent hypercortisolism will not^27,45,46 (Fig. 7-6).

In the past, tests such as stimulation with metyrapone or suppression with high-dose dexamethasone have been employed to distinguish between adrenal and pituitary Cushing’s syndrome,⁴⁷ but their suboptimal specificity has superseded their routine use for this purpose. However, the high-dose dexamethasone suppression test has been re-proposed for the etiologic diagnosis of adrenal Cushing’s syndrome (see later).

Differential Diagnosis of Adrenal Causes of Cushing’s Syndrome

The etiology of adrenal Cushing’s syndrome is usually established by imaging of the adrenals (see also Chapter 10), since biochemical and clinical features overlap considerably between adenoma, carcinoma, and adrenal hyperplasia.^7,14,16 Hormonal measurements provide useful adjunctive information but rarely establish the diagnosis with certainty. Genetic causes, such as PPNAD or MAS, may be recognized by features typical to the syndrome (e.g., lentigines or myxomas and fibrous osseous dysplasia, respectively; see later).

Inherited Familial Syndromes

Adrenocortical tumors can be encountered in a number of genetic syndromes, such as multiple endocrine neoplasia (MEN) type 1, MAS, familial adenomatous polyposis and Carney’s complex.

Steroidogenic Enzymes in Adrenal Lesions

Several studies have evaluated steroidogenesis in adrenal Cushing’s syndrome. Cortisol concentration in tumoral specimens is 2- to 50-fold greater in adenomas than in normal glands,¹⁵⁶ attesting to the greater secretory output. Steroidogenesis usually proceeds without hindrance to its principal end product, cortisol, but individual steroidogenic enzymes may become rate-limiting in hypersecreting adrenals,¹⁵⁷ the extent and involvement of individual enzymes being quite variable. Analysis of steroidogenic enzymes yielded somewhat conflicting results, with increased 21-hydroxylase and 17α-hydroxylase synthesis and activity in cortisol-secreting adenomas as the most constant finding.^112,156,158 Increased 17,20-lyase activity reportedly occurs in adenomas producing androgens in addition to cortisol, possibly a consequence of increased cytochrome b₅ expression.¹⁵⁹ A relative deficiency of 11β-hydroxylase has been suggested by some authors,¹⁶⁰ although not confirmed by others.¹⁵⁸ Conversely, 3β-hydroxysteroid dehydrogenase and cholesterol desmolase appear substantially unchanged in cortisol-secreting adenomas.^112,158 In adrenal carcinoma, cortisol secretion per gram of tumoral tissue is mostly reduced,¹⁶⁰ as are individual steroidogenic enzymes.^28,112,161 Of interest, malignant cells may fail to synthesize the full complement of steroidogenic enzymes,^28,161 thus possibly explaining ineffective steroidogenesis. Shift from excess aldosterone to excess cortisol production has also been reported in malignant tumors, associated with changes in steroidogenic enzyme synthesis and attesting to the plasticity of tumoral tissues.¹⁶² The low efficiency of cortisol secretion is also a feature of macronodular hyperplasia,¹⁰⁰ and variable expression of steroidogenic enzymes in individual cortical cells has been observed.¹⁶³ In contrast, nodules from patients with PPNAD all present intense immunostaining for steroidogenic enzymes.¹⁶³ Lastly, low levels of expression and activity of 11β-hydroxysteroid dehydrogenase type 2, the enzyme which inactivates cortisol, have been detected in adenomatous cortisol-secreting adrenals and may represent an additional modulator of total cortisol levels.^164,165

Regulation of Steroid Synthesis in Adrenal Lesions

In adrenal Cushing’s syndrome, cortisol secretion is by definition ACTH-independent. However, a considerable proportion of adenomas, and to a lesser extent carcinomas, maintain ACTH-responsiveness in vivo and in vitro,7,166 and the relevance of this preserved ACTH sensitivity in tumors which secrete cortisol autonomously remains unclear. The ACTH receptor (also known as the melanocortin 2 receptor, MC2-R) is expressed in the vast majority of cortisol-secreting adenomas, even overexpressed compared with the normal adrenal cortex, according to some authors,^166,167 whereas cortisol-secreting carcinomas present low levels of MC2R mRNA, possibly a consequence of dedifferentiation and loss of heterozygosity at this locus.¹⁶⁷ ACTH is known to up-regulate its own receptor at low concentrations and exert the opposite effect at higher doses,¹⁶⁸ but no direct association between ACTH receptor mRNA and ACTH plasma levels has been detected in various forms of Cushing’s syndrome.¹⁶⁹ Stimulation of steroid secretion in adrenocortical tumor cells occurs through activation of protein kinase C, together with the main protein kinase A–cAMP pathway.¹⁷⁰ Of interest, factors other than ACTH may also increase cAMP levels in malignant but not in normal adrenal cells, as has been demonstrated for catecholamines and thyrotropin,¹⁷¹ indicating a loss of specificity of the transductional machinery in tumoral tissues (see heading ACTH-Independent Adrenal Hyperplasia). Moreover, ACTH is also an indirect adrenocortical mitogen acting through factors such as basic fibroblast growth factor (bFGF), insulin-like growth factor 2 (IGF-2), epidermal growth factor (EGF), and transforming growth factor (TGF) α or β.^172,173 These mediators are responsible for the growth-promoting effect of ACTH in vivo, whereas in vitro, ACTH exerts a direct antimitogenic activity.¹⁷² Similarly divergent are the effects of N-terminal pro-opiomelanocortin (POMC), which appears to stimulate mitogenic activity via the secretory serine protease (AsP) pathway in vitro¹⁷⁴ but is devoid of mitogenic effects in Pomc-null mice in vivo.¹⁷⁵

One brief mention is warranted for the regulation of cortisol synthesis by corticosteroids themselves. Evidence for this ultra-short negative feedback has been garnered by in vivo and in vitro studies, although paradoxically, a stimulatory, permissive effect of cortisol or dexamethasone on ACTH-stimulated cortisol secretion has been reported by some authors.¹⁷⁶ The direct action of corticosteroids on steroidogenesis is presumably mediated by glucocorticoid receptors themselves, since both binding and induction of gene synthesis have been demonstrated in the adrenal cortex.^167,177 Expression of the glucocorticoid receptor is apparently reduced in cortisol-secreting tumors.^167,178

Pathogenesis

ACTH-independent adrenal hyperplasia presents a heterogeneous etiology, comprising legitimate and illegitimate adrenal growth factors and gene mutations. In one of the first descriptions of ACTH-independent adrenal hyperplasia, proliferation of small cortical cells with maturational arrest or incomplete maturation was hypothesized to cause hyperplasia.¹⁰⁰ Causes identified so far, however, account for only part of reported patients, and other mechanisms are likely to be involved. Indeed, microarray studies in AIMAH tissues identified a host of potential candidate genes,^191,192 in part overlapping with genes involved in adrenal tumorigenesis, such as the Wnt signaling pathway, and cytogenetic analysis revealed frequent allelic losses in 2p16 and 17q22, two sites linked to PPNAD,¹⁴⁰ in adrenal hyperplastic tissues.

Treatment

Removal of both adrenal glands is obviously the rational approach to curing hypercortisolism in this condition. Laparoscopic adrenalectomy of glands measuring up to 13 cm has been reported, indicating that size need not be a concern in this benign lesion.²⁴⁴ Likewise, development of Nelson’s syndrome has not been reported in patients with ACTH-independent adrenal hyperplasia. Alternative approaches, such as subtotal or unilateral adrenalectomy, may be considered in selected patients. To avoid risks associated with adrenal insufficiency,²⁴⁵ subtotal adrenalectomy has been performed in a patient with multiple malignancies, whereas removal of the largest adrenal achieved long-term remission in several patients with asymmetric involvement.^189,246 Transitory hypoadrenalism requiring steroid replacement therapy may occur. Should abnormalities in HPA function persist, as appears to occur in patients with comparable enlargement of both adrenal glands, removal of the contralateral gland may be performed,²⁴⁶ or medical therapy with antagonists to illicit receptors may be used to restrain hypercortisolism.¹³ Surgery may not be advisable in all patients with AIMAH, given the often advanced age at diagnosis and the attendant, age-related comorbidities. Thus, administration of steroid synthesis inhibitors may be the treatment of choice, and relatively low doses of steroid blocking agents are usually capable of containing hypercortisolism in these patients. In addition to ketoconazole, metyrapone and mitotane have also been administered with success.^247,248

Pathogenesis

The initial pathogenic hypothesis for PPNAD was based upon the finding of adrenal-stimulating antibodies in sera of patients with PPNAD.92,252 These studies revealed that DNA synthesis, adrenal growth, and cortisol release can be stimulated by circulating immunoglobulins present in patients with PPNAD.^92,110,252 Stimulating immunoglobulins were present independent of the presence of hypercortisolism, suggesting that these antibodies contribute but are not the sole mediator of increased adrenal activity.²⁵² No additional autoantibodies were detected in sera of affected patients, underlining the specificity of the phenomenon. However, adrenal-stimulating antibodies are not an invariable finding in patients with PPNAD.²⁵³ Studies on resected adrenals showed that nodules present intense immunostaining for steroidogenic enzymes and secrete cortisol in normal amounts.^163,254 Steroidogenesis appears to be extremely sensitive to inhibition by ketoconazole in vitro²⁵⁴ and increases paradoxically during incubation with dexamethasone.²⁵⁵ This increase, which may occur also in adrenal adenomas (see earlier) and most likely accounts for the paradoxical responsiveness to high-dose dexamethasone in vivo, has been attributed to the intense expression of the glucocorticoid receptor.²⁵⁵

The advent of molecular biology shifted the focus to chromosomal and genetic alterations, leading to the identification of specific chromosomal loci and the first causative genetic alteration. Linkage studies revealed strong LOD scores (≥5.9) for a 6.4 cM region on the short arm of chromosome 2²⁵³ and a 17 cM locus on the long arm of chromosome 17.²⁵⁶ In keeping with the genetic heterogeneity of Carney’s complex, some kindreds map to both loci and others do not segregate to either, thus further sites remain to be identified. The region on chromosome 2 is known to harbor genes involved in tumor suppression and cell-cycle progression, and both genetic losses and gains at 2p16 (Carney complex 2 locus, CNC2) have been reported, suggesting the presence of oncogenes which await definition.²⁵⁷ Conversely, loss of heterozygosity at 17q22-24 hinted at a possible tumor-suppressor gene, narrowing the field of candidate genes and leading to the detection of mutations in the protein kinase A regulatory subunit 1 alpha (PRKAR1A) gene, a mediator involved in inhibition of cAMP signaling.^154,155 PRKAR1A spans 11 exons and gives rise to a 2890-bp mRNA species, which in turn is translated into a 381-amino-acid protein (Fig. 7-15B). Heterozygous germline mutations in PRKAR1A (Carney complex 1 locus, CNC1) have been detected so far in nearly half of known kindreds with Carney’s complex as well as in patients with “sporadic” PPNAD.^155,249 Gene alterations are mostly nonsense point mutations or frameshift mutations with premature stop codons, more rarely large deletions, leading to null alleles due to nonsense-mediated degradation of mutant mRNA or to truncated proteins^154,155,258 (see Fig. 7-15B; Table 7-5). Indeed, the amount of PRKAR1A protein is nearly halved in lymphocytes from patients with Carney’s complex compared to normal subjects, reflecting expression of the wild-type allele only.¹⁵⁴ More rarely, PRKAR1A mutated genes are transcribed and result in mutant or reduced amounts of protein.²⁵⁹ The PRKAR1A protein is part of the protein kinase A holoenzyme, consisting in two regulatory and two catalytic subunits (see Fig. 7-15A). The tetramer is inactive and requires binding of cAMP to regulatory subunits for catalytic subunits to dissociate and phosphorylate target proteins which in turn will activate downstream events. The two regulatory subunits (R1 and R2) each present two isoforms, alpha and beta, with different tissue-specific patterns of expression. Activity of PKA is dependent upon the availability of free catalytic subunits as well as on the ratio of R1:R2 regulatory subunits, and R1-alpha appears crucial for protection against excessive catalytic activity.²⁶⁰ In patients with Carney’s complex, haploinsufficiency of PRKAR1A due to nonsense-mediated mRNA decay or presence of mutant PRKAR1A proteins, leads to increased basal/stimulated PKA activity in adrenal cells,^155,259,261 which in turn affects downstream signaling. The effects exerted by cAMP-stimulated PKA activity vary in different tissues, from growth promotion in pituitary and thyroid adenomas to differentiation of cardiac cells and inhibition of proliferation in Schwann cells. Of interest, PRKAR1A mutations appear to be more frequent in patients with Carney’s complex who develop PPNAD,²⁶¹ and specific mutations have been shown to recur in patients with sporadic PPNAD.²⁶² However, there is no clear genotype-phenotype correlation, and other disease-modifying loci most likely contribute to the clinical presentation. In this context, deletions and amplifications of CNC2 at chromosome 2p16 have also been observed in patients with PRKAR1A mutations.²⁵⁷

Interestingly, somatic PRKAR1A mutations have been observed in patients with pigmented adrenal adenoma¹³⁹ but none in patients with classic macronodular adrenal hyperplasia.¹⁴⁰ Among other enzymes involved in the cAMP-signaling cascade, phosphodiesterase 11A has recently been linked to both bilateral adrenocortical hyperplasia and dysplasia, and available evidence suggests germline mutations in PDE11A are low-penetrance predisposing factors for these and other tumors.²⁶³ Mutation of another phosphodiesterase, PDE8B, has been detected in a young girl with Cushing’s syndrome due to micronodular adrenal hyperplasia.²⁶⁴

Treament

Bilateral adrenalectomy is the treatment of choice for PPNAD, since both adrenals are affected. The risk of Nelson’s syndrome is nonexistent; plasma ACTH levels may not even rise above the normal range after removal of the adrenal glands.²⁶⁵ Patients with minimal hypercortisolism have occasionally been treated with unilateral adrenalectomy, and this has proven curative in some^12,77; in others, however, removal of the remaining adrenal was necessary to contain hypercortisolism.^12,266 In patients submitted to removal of a single adrenal gland, subtle alterations of HPA function, such as disruption of cortisol circadian rhythm, may persist^26,41,267 and lead to progressive development of Cushingoid features over time.²⁶⁷ Medical adrenalectomy has been obtained in a patient treated with o,p’DDD for some 3 years, followed by remission of hypercortisolism for over 12 years.¹² Brief treatments with low doses of adrenal blocking agents such as ketoconazole may prove beneficial prior to surgery. Spontaneous resolution has also been reported, most notably the first case described by Carney.^12,76

Childhood

Cushing’s syndrome in children is most often due to adrenocortical neoplasms, with PPNAD and MAS accounting for a scattering of cases.²⁸¹ Adrenal cancer is an extremely rare pediatric malignancy (0.3 to 0.4 per million children per year) except for a population in southern Brazil, where this tumor is approximately 10 times more frequent than in the rest of the world (3.4 to 4.2 per million children per year).²⁸² Tumors arise mostly in preschool children (before 5 years of age) and present a slight female preponderance.^29,282 In contrast to adult adrenocortical tumors, over 80% of childhood adrenal tumors are functional, and cortisol hypersecretion is almost invariably accompanied by enhanced production of androgens and thus virilization. Functioning adrenocortical tumors have even been encountered at birth.²⁸² Children may present with temporal balding, acne, the appearance of pubic and axillary hair, precocious puberty, increased muscle mass, accelerated height, increased body weight (Fig. 7-17), moon facies, hypertension, and electrolyte imbalances.^29,282 Bone age is usually advanced except in those rare cases of “pure” Cushing’s syndrome.²⁹ Detection of increased 17-ketosteroids or DHEAS is virtually diagnostic for adrenocortical tumor, and imaging procedures such as sonography, CT, or MRI easily reveal its presence.^29,282

Pathologic classification of tumors on the basis of commonly used algorithms (i.e., Weiss, Hough, van Slooten) does not provide a clear distinction between benign and malignant lesions in childhood adrenal cancer.²⁸³ Indeed, Weiss grade III or IV tumors exhibit an unusually benign course in children,²⁸⁴ and tumor size, weight, and invasion of adjacent organs appear to be more predictive of malignant behavior than classic histologic features.^284,285 Postsurgical survival ranges between 56% and 70% at the 5-year landmark.^282,284 Treatment with o,p’DDD has been carried out in several children, albeit with significant neurologic side effects and high risk of adrenal insufficiency, whereas reports on efficacy of chemotherapeutic regimens are few.^281,285

PPNAD and MAS, the other possible causes of hypercortisolism in childhood and adolescence, are usually readily apparent because of the presence of associated features (see specific sections). Bilateral adrenalectomy provides ready relief from symptoms and usually allows catch-up growth.²⁸⁶

Pregnancy

Cushing’s syndrome is often associated with oligomenorrhea and anovulation, thus pregnancy very rarely occurs in hypercortisolemic women. However, several cases have been reported with considerable maternal morbidity and high fetal wastage, so prompt diagnosis and correction of hypercortisolism are therefore necessary. Urinary free cortisol is usually clearly elevated in pregnant hypercortisolemic women, and there is little risk of overlap with physiologically increased UFC levels during gestation.²⁸⁷ By contrast, cortisol suppression after low-dose dexamethasone is impaired during normal pregnancy, and cutoffs for diagnosis of Cushing’s syndrome have to be adapted.^81,287 Establishment of the cause of hypercortisolism follows usual procedures, with ACTH levels normally suppressed in adrenal Cushing’s syndrome and imaging procedures (sonography or MR) usually enabling visualization of the adrenal lesion.²⁸⁸ Both malignant and benign lesions, the latter including also AIMAH and PPNAD, have been reported during pregnancy, thus none can be excluded a priori. Interestingly, among patients with Cushing’s syndrome diagnosed during gestation, adrenal causes account for over half of reported cases, which is considerably more than in the nonpregnant state.⁸¹ In some cases, cortisol levels increased after βhCG administration, and hypercortisolism resolved spontaneously after delivery,^35,36 suggesting the involvement of aberrant LH/hCG receptors (see heading ACTH-Independent Adrenal Hyperplasia). To what extent these receptors account for the increased frequency of adrenal adenoma and hyperplasia during pregnancy remains to be established. Treatment of hypercortisolism during pregnancy is diversified according to the stage of gestation, with surgical removal of the adrenal lesion preferred during the first half of pregnancy and medical treatment with ketoconazole in the last trimester, although the converse approach also yielded favorable outcome.²⁸⁹

Surgery

Surgery is straightforward and usually curative in benign adrenal causes of Cushing’s syndrome (i.e., adenoma, PPNAD, and AIMAH). Conversely, malignant lesions require extensive resection of the lesion without, however, guaranteeing cure.

Removal of the adrenal adenoma is followed by remission of hypercortisolism, and long-term survival becomes comparable to that of the general population.104,290 Exceptionally, Cushing’s syndrome may recur due to bilateral or ectopic adrenal adenomas^290,291 or, as has also been reported, development of adrenal carcinoma on the same site of a previously resected adrenal adenoma.¹¹⁷ Alternative surgical approaches, such as percutaneous acetic acid injection, radiofrequency ablation, adrenal arterial embolization, and adrenal-preserving minimally invasive surgery have been attempted with variable success in cortisol-secreting adenomas.^292–295 The drawback of these procedures is the absence of specimens for pathology, thus the preoperative diagnosis has to be certain.

In adrenal cancer, surgery is part of a multimodal approach also comprising chemotherapy and adrenolytic drugs. Only complete resection of the tumor offers potential for cure, although recurrence is not infrequent, sometimes after decades. On the whole, outcome is not encouraging, with less than 40% survival at the 5-year landmark²⁵ without significant differences between functional and nonfunctional adrenal carcinomas. In hypersecreting malignant tumors, steroid hormone levels (e.g., DHEAS, UFC, estrogen, and 11-deoxycortisol) and plasma ACTH concentrations can be used as markers for residual disease and recurrence. For a detailed discussion of this topic, the reader is referred to Chapter 11.

Surgical procedures evolved from open surgery, via epigastric or subcostal transabdominal access or posterior lumbar extraperitoneal approach, to modern laparoscopic techniques, with a decrease in perioperative morbidity and mortality.²⁹⁶ This is nowadays the procedure of choice for removal of benign lesions in one or both adrenal glands, except for patients with coagulopathies, previous local surgery, or huge hyperplastic adrenals which necessitate long surgical procedures^296,297 (see also Chapter 15). Adrenal cancer should be operated via laparoscopy only if this ensures wide margin resection of the tumor; most surgeons still prefer transabdominal access because this allows maximal exposure of the tumor and affected organs or vessels, in particular to tumor thrombi in the inferior vena cava, and minimizes the chance of tumor spillage.

Removal of the hyperfunctioning adrenal tissue is followed by a 1- to 2-year period of adrenal insufficiency due to pituitary-mediated inhibition of the normal adrenal gland.298,299 Steroid replacement therapy has to be administered (hydrocortisone 15 to 25 mg, two or three daily doses) and tapered over time according to recovery of the HPA axis. The latter, as well as the adequacy of steroid dosage, are largely established by clinical assessment rather than biochemical parameters.³⁰⁰ These include morning serum cortisol concentrations (levels greater than 10 µg/dL) or cortisol response to exogenous ACTH (peak response ≥20 µg/dL). Interestingly, several patients have been reported in whom the HPA axis never fully recovered and replacement therapy could not be discontinued.¹⁶

Bilateral adrenalectomy is the treatment of choice for AIMAH and PPNAD, with few exceptions (see related sections). Removal of the adrenal glands is easily performed using laparoscopy in PPNAD, whereas open surgery may be required if glands are extremely big in patients with AIMAH.182,266 Obviously, patients have to be started on lifelong steroid replacement therapy immediately after surgery, and usual precautions for adrenal insufficiency (see Chapter 6) are strenuously recommended; inappropriate treatment of adrenal crisis contributes significantly to mortality in these patients.

Medical Therapy

Drugs used for containment of hypercortisolism may be classed into three groups: adrenolytic, adrenostatic, and glucocorticoid receptor antagonists. Adrenolytic drugs—that is, compounds that destroy adrenocortical cells in addition to restraining steroid synthesis—are used mainly in adrenocortical cancer, whereas drugs that interfere with steroidogenesis without damaging adrenal cells (i.e., adrenostatic) can be used in any etiology of Cushing’s syndrome and also in pituitary-driven or ectopic ACTH-driven hypercortisolism. Lastly, the progesterone and glucocorticoid receptor antagonist mifepristone (RU486) has been employed to relieve symptoms related to severe hypercortisolism in a scattering of cases but has never entered mainstream antiglucocorticoid therapy. The effect of these drugs is not always predictable, thus expert handling, with close monitoring of efficacy and side effects, is necessary.³⁰¹ On balance, metyrapone and ketoconazole are the drugs of choice for the medical containment of hypercortisolism, whereas other adrenostatic compounds are little used except for intravenous etomidate in severe Cushing’s syndrome. Mitotane (o,p’DDD) is indicated in adrenal cancer.

Medical therapy for illicit receptor–driven hypercortisolism has been discussed previously (see heading ACTH-Independent Adrenal Hyperplasia). On the whole, the use of specific receptor antagonists—while theoretically the most rational approach—is limited by its incomplete efficacy and the ease and feasibility of adrenalectomy. It may be employed in patients with mild hypercortisolism or after unilateral adrenalectomy to delay restrictions imposed by surgical adrenal insufficiency.

Chemotherapy, usually together with mitotane, is used in advanced-stage adrenal cancer, but experience is still limited.23,25 This and other topics related to oncologic aspects of adrenal cancer are discussed in Chapter 11.

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4. Carpenter, PC. Diagnostic evaluation of Cushing’s syndrome. Endocrinol Metab Clin North Am. 1988;17:445–472.

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